In microbiology, a large number of methods are known for the study of pathogenic microorganisms on the basis of cell culture and antibiotic resistance tests. The “phenotypic” approach, in which the action such as for example the growth or the inhibition of cell growth is studied, is advantageous. Via the action on cell cultures, a direct reference to the action on man or animals can be obtained. In this, cell cultures are placed for days on end in a nutrient solution, for example in Petri dishes, and observed. The growth or the damage to the cell cultures is measured and assessed over long periods. The long periods which are necessary for the observation make the method very costly and prolonged.
For the measurement of the growth or the damage to the cell cultures, sensor systems can be used. Living cells are for example grown on sensors in order then to monitor the vitality of the cells for example by measurement of impedance, oxygen (pO2) or pH. As sensors, interdigital electrode arrays, oxygen sensors or pH sensors can be used. Measures of the vitality of the cells are inter alia their adhesion to surfaces, their respiration or their metabolism. However, growing the cells on the sensors is time-consuming and leads to limited storability of the sensor systems. Cells that have grown on the sensors can migrate on the surface and/or die off.
For measurement of the vitality of cells via an oxygen or pH value, it is necessary that living cells be situated in direct proximity to the sensors. Only thus can it be ensured that concentration changes of starting substances or reaction products of the cell metabolism are recorded by the sensors. Here, direct growth of the cells onto the electrodes must be prevented, since for a reliable measurement, for example by electrochemical sensors, a liquid film must be present between cell wall and sensor surface.
Cells have a size in the micrometer range. Normal electro-chemical sensors have metal surfaces which are for example made in the form of comb-shaped interpenetrating inter-digital electrodes, with a circular overall sensor perimeter. The diameter of such a sensor as a rule lies in the region of several millimeters. In order to prevent crosstalk of the sensors, the sensors have a distance between one another which likewise lies in the millimeter range. Wall-shaped ridges are often formed between sensors, in order to obtain better separation of the sensors from each other and assignment of signals to regions over the sensors and effectively to suppress crosstalk.
Through their metabolism, individual living cells cause only slight changes in the concentration of chemical and biochemical substances in their vicinity. These slight concentration changes are only measurable if sensors have a high sensitivity for the substance and the cells are arranged close enough to the sensors. Sensors with an overall diameter in the millimeter range can only with difficulty attain a sensitivity that suffices for measuring metabolic products from single cells. Side reactions on large electrode areas lead to poor signal-to-noise ratios. A large distance between the sensors can have the result that cells are located between the sensors and no signals from the cells can be measured.
The distance between the midpoints of two sensors or the highest possible packing density of sensors of a sensor array is also determined by the contacting and arrangement of signal-processing circuits. Thus, with the use of semiconductor supports, integrated circuits can be arranged directly under the sensors. The integrated circuits can be formed for each sensor under the respective sensor, for example with the use of CMOS technology in the silicon support material. The size of a circuit then determines the greatest possible packing density of the respectively assigned sensors of the sensor array lying above it. A common integrated circuit for measuring electro-chemical signals from a sensor has a space usage or an area in the sensor array support which lies in the millimeter range. In particular, the creation of operational amplifiers in integrated circuits leads to a high space usage.